The present invention is directed to compositions useful as nutritional supplements and to methods of improving the well-being of mammals ingesting such compositions, particularly their ability to assist in the production, maintenance and repair of bone and bone structures in the body.
Derivatives of collagen and bone have long been used in the surgical repair of bone defects and bone trauma in mammals. For example, in 1899, Senn showed healing of experimental canine calverial defects and of human tibial and femoral defects with decalcified ovine bone. Others have shown bone formation in periapical areas in dogs and monkeys and in skull defects in rats after implantation or demineralized bone by itself. The osteogenic potential of demineralized bone powder has been demonstrated in cranial osseous defects in rats.
In 1931, Huggins (Arch. Surg., 22:377-408) reported that proliferating mucosa of Kidney, ureter, or bladder induced bone formation when implanted in connective tissue. This was the first reported experimental model of induced ectopic osteogenesis. More recently, Urist (Science, 150: 893-899, 1965) and Reddi et al (Proc. Natl. Acad. Sci. U.S.A., 69: 1601-1605, 1972) demonstrated that osteogenesis could also be induced by the acellular, demineralized matrix of bone or dentin. It has been shown that physical factors, including surface charge and geometry of the matrix, are involved, Reddi et al (Proc. Natl. Acad. Sci. U.S.A., 69: 1601-1605, 1972). There is evidence that a soluble factor from demineralized bone, bone morphogenetic protein, is osteoinductive; see Urist et al, Proc. Natl. Acad. Sci. U.S.A., 76: 1828-1932, 1979. Thereafter, Mulliken reported on the use of demineralized bone segments, chips, and powder for reconstruction of craniofacial defects in rats and humans; see Mulliken et al. Plast. Reconstr. Surg., 65: 533-559, 1980 and Glowacki et al, Lancet, May 2, 1981, 963-966. Furthermore, the glycoprotein, bone morphogenetic protein (BMP), has been characterized and is reported to have induced new bone formation in rats. Additionally, BMP's action does not appear to be species-specific; rabbit BMP has induced new bone formation in rats and bovine bone BMP is functional when surgical repair products derived from bovine sources are used in humans.
A variety of methods and compositions of biomaterials have been used to repair or regenerate bone loss due to either trauma or disease. Conventional implantable bone repair materials provided a matrix or scaffolding for migration into, proliferation and subsequent differentiation of cells responsible for osteogenesis (Nashef U.S. Pat. No. 4,678,470). While the compositions provided by this approach provided a stable structure for invasive bone growth, they did not promote bone cell proliferation or bone regeneration. Generally, these materials are referred to as osteoconductive.
Subsequent approaches have used bone repair matrices containing bioactive proteins which when implanted into a bone defect provided not only a scaffolding for invasive bone ingrowth, but active induction of bone cell replication and differentiation. These materials are generally referred to as osteoinductive.
In general, osteoinductive compositions comprise a matrix which provides the scaffolding for invasive growth of the bone, anchorage dependent cells, and an osteoinductive protein source. The matrix may be a variety of materials, such as: collagen (Jefferies U.S. Pat. Nos. 4,394,370 and 4,472,840); inorganically based materials, such as a biodegradable porous ceramic (Urist U.S. Pat. No. 4,596,574); or, polylactic acid (Urist U.S. Pat. No. 4,563,489).
Osteogenic compositions and methods for making the same are described in Jefferies U.S. Pat. Nos. 4,394,370 and 4,472,840. Jefferies describes complexes of reconstituted collagen and demineralized bone particles or complexes of reconstituted collagen and a solubilized bone morphogenetic protein, fabricated into a sponge suitable for in vivo implantation into osseus defects. Structural durability of these compositions may be enhanced by crosslinking with glutaraldehyde.
In particular, two specific substances have a well-established ability to induce the formation of new bone (i.e., to be osteoinductive) through the process of osteogenesis: demineralized bone particles or powder, and bone morphogenetic proteins (BMPs) (Urist U.S. Pat. Nos. 4,595,574, 4,563,489, 4,551,256). A variety of other bone inducing factors have been characterized and claimed for various uses (Seyedin et al., U.S. Pat. Nos. 4,627,982; 4,774,228; 4,774,322; 4,810,691 (RE34090); and 4,843,063 (RE35694)).
Bone derivatives and bone products have been disclosed as useful for other than implant or surgical applications. U.S. Pat. No. 6,344,437 describes method of enhancing bone strength by orally administering a composition of degraded collagen, calcium and vitamin D.sub.3 (claims 1, and 2 and 3). Demineralized bone protein fraction (fraction D, Reference Example 4) was not used for any orally administerable composition. Furthermore, the patent teaches that calcium is to be used in combination with the bone derivative.
U.S. Pat. No. 4,427,583 discloses a countercurrent flow process for demineralizing animal bone in order to prepare an edible ossein protein product. The patent discloses various chemical processing steps for obtaining a demineralized bone product but there is no disclosure of any edible uses or effects.
Romanian Patent 90,405 (Oct. 30, 1986) discloses a “biostimulating and remineralizing product” for use in the treatment of “demineralizing organic conditions.” (See translation, page 1.) The product composition includes “protein depleted bone minerals” (See page 2) obtained from “total cattle bone powder.” The total cattle bone powder and protein depleted minerals are mixed with ingredients to provide “a pleasant sweet taste” and further includes royal jelly, dried rose hip jam, honey, and tamarisk jam in order to produce an edible composition. Additionally, it is noted that the product specifically includes “1.5 parts sodium fluoride,” which is equal to about 1.5 wt % based on the formulation disclosed (See page 2).